Leptin, the product of the ob gene is a hormone produced by the adipose tissue that inhibits food intake and increases energy expenditure in rodents. In humans, plasma leptin concentration correlates closely with the size of the adipose tissue depot; however, there is considerable variation in plasma leptin concentration at any given degree of fatness. Results among Pima Indians indicate that large weight gainers have relatively lower plasma leptin concentration than Pimas whose weight is stable. These data indicate that relatively low plasma leptin concentrations may play a role in the development of obesity in Pima Indians. Our studies in Pimas and Caucasians indicate: subjects with insulin resistance and hyperinsulinemia have higher plasma leptin concentration than subjects with normal insulin sensitivity; insulin acutely increases expression of leptin mRNA in the adipose tissue; in relatively lean individuals, the administration of therapeutic doses of glucocorticoids does not influence plasma leptin concentration; the beta3 adrenoceptor variant previously described is not associated with plasma leptin concentration; menstrual abnormalities in young premenopausal women seem to occur as a consequence of the linear decline in adiposity and plasma leptin concentration in response to inadequate nutritional status; a polymorphism at amino acid 223 of the leptin receptor is associated with NIDDM and lower plasma leptin concentrations. Subjects homozygotes for the ARG223 have low cerebrospinal fluid leptin concentration relative to plasma concentration when compared to subjects heterozygote or homozygote for GLN223; in five-year-old Pima Indian children, plasma leptin concentration correlates positively with total energy expenditure and with physical activity; in male Pima Indians, low plasma leptin concentrations are associated with low rates of lipid oxidation and ; post-obese women (biliopancreatic diversion) have higher energy intake and lower plasma leptin concentration than morbidly obese and normal weight women. Taken together, these results suggest that hypoleptinemia may promote body weight gain or relapse (after weight loss) in humans by increasing food intake and decreasing energy expenditure.